This project has been mapping the brain regions involved in emotion recognition and regulation in health and disease using two different but related 'activation' methods. In one series of studies we have imaged depressed subjects and controls using O15 PET and fMRI while they performed neuropsychological tasks specifically designed to activate and test the function of important brain regions involved in emotion modulation. Dr. Mark George has completed a facial emotion recognition study, an emotional Stroop study, a prosody study, and we are continuing a sadness induction paradigm in both patients and volunteers. The second method involves actually stimulating the brain regions important in mood recognition or regulation and assessing differences in mood; this is done using rapid transcranial magnetic stimulation (rTMS). In collaboration with NINDS investigators, we are studying with 18-FDG PET the neural substrate affected by both rapid and single pulse TMS. Significant findings to date include the following: 1) We have demonstrated key brain regions involved in emotion recognition from several sensory modalities (faces, spoken language). 2) During transient sadness, healthy adults activate the anterior limbic system. Women, compared with men, activate more of the limbic system despite similar performance. During happiness, they activate only the anterior cingulate and deactivate numerous areas in secondary association cortex. 3) Depressed subjects, both while actively depressed and when clinically recovered and in remission, have difficulty inducing transient happiness or sadness or returning to baseline once these emotions are achieved. Additionally, these patient populations have blunted anterior limbic activation as measured by rCBF with sadness induction. 4) Stimulation of the left prefrontal cortex in healthy controls results in mild increases in sadness, with right stimulation giving increases in happiness. 5) Prefrontal, and not occipital, stimulation causes increases in serum TSH with findings apparently opposite to those in depressed patients with left frontal rTMS, is associated with improvement, with no changes in prolactin or cortisol. 6) Chronic daily left prefrontal stimulation improves depressive symptoms in patients who are resistant to multiple antidepressant medications. 7) Prefrontal and motor strip stimulation produces both local and remote brain effects which can be demonstrated on FDG PET scanning.